Recurrent activating mutations of PPARγ associated with luminal bladder tumors.

Date publication

janvier 2019

Journal

Nature communications

Auteurs

Membres identifiés du Cancéropôle Est :
Dr CIANFERANI Sarah , Dr DEJAEGERE Annick , Pr LANG Hervé , Dr MASSFELDER Thierry , Dr ROCHEL-GUIBERTEAU Natacha , Dr OSZ-PAPAI Judit

Tous les auteurs :
Rochel N, Krucker C, Coutos-Thévenot L, Osz J, Zhang R, Guyon E, Zita W, Vanthong S, Hernandez OA, Bourguet M, Badawy KA, Dufour F, Peluso-Iltis C, Heckler-Beji S, Dejaegere A, Kamoun A, de Reyniès A, Neuzillet Y, Rebouissou S, Béraud C, Lang H, Massfelder T, Allory Y, Cianférani S, Stote RH, Radvanyi F, Bernard-Pierrot I

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/30651555

Résumé

The upregulation of PPARγ/RXRα transcriptional activity has emerged as a key event in luminal bladder tumors. It renders tumor cell growth PPARγ-dependent and modulates the tumor microenvironment to favor escape from immuno-surveillance. The activation of the pathway has been linked to PPARG gains/amplifications resulting in PPARγ overexpression and to recurrent activating point mutations of RXRα. Here, we report recurrent mutations of PPARγ that also activate the PPARγ/RXRα pathway, conferring PPARγ-dependency and supporting a crucial role of PPARγ in luminal bladder cancer. These mutations are found throughout the protein-including N-terminal, DNA-binding and ligand-binding domains-and most of them enhance protein activity. Structure-function studies of PPARγ variants with mutations in the ligand-binding domain allow identifying structural elements that underpin their gain-of-function. Our study reveals genomic alterations of PPARG that lead to pro-tumorigenic PPARγ/RXRα pathway activation in luminal bladder tumors and may open the way towards alternative options for treatment.

Mots clés

Cell Line, Tumor, Cohort Studies, Crystallography, X-Ray, Female, Gain of Function Mutation, HEK293 Cells, Humans, Male, Molecular Dynamics Simulation, PPAR gamma, chemistry, Protein Interaction Domains and Motifs, genetics, Retinoid X Receptor alpha, genetics, Sequence Analysis, DNA, Signal Transduction, genetics, Structure-Activity Relationship, Urinary Bladder, pathology, Urinary Bladder Neoplasms, genetics

Référence

Nat Commun. 2019 Jan 16;10(1):253